Compounds that contain the 5-acetamidomethyl-oxazolidinone moiety are well known to persons skilled in the art as pharmacologically useful antibacterial agents. For example, U.S. Pat. Nos. 5,164,510, 5,182,403, and 5,225,565 disclose antibacterial 5′-indolinyl-oxazolidinones, 3-(5′-indazolyl)-oxazolidinones, and 3-(fused-ring substituted)phenyl-oxazolidinones, respectively. Similarly, U.S. Pat. Nos. 5,231,188 and 5,247,090 disclose several tricyclic [6.5.5] and [6.6.5]-fused ring-oxazolidinones which are useful pharmaceutical agents. International Publication WO93/09103 discloses antibacterial mono- and di-halophenyl-oxazolidinones.
Persons skilled in the art use two primary methods to prepare the 5-acetamidomethyl-oxazolidinone moiety of these therapeutic agents. The first method involves condensation of an aromatic carbamate (Ar—HN—C(═O)—OR) or aromatic isocyanate (Ar—N═C═O) with a halopropanediol or another nitrogen-free three-carbon reagent to provide an intermediate oxazolidinone having a hydroxymethyl substituent at the C-5 position of the oxazolidinone. The hydroxyl group then is replaced by an acetamido group to give a pharmacologically active 5-acetamidomethyl-oxazolidinone.
Many variants of this two-step process have been developed, and examples are illustrated in U.S. Pat. Nos. 4,150,029, 4,250,318, 4,476,136, and 4,340,606, which disclose the synthesis of 5-hydroxymethyl-oxazolidinones from amines (Scheme A). The mixture of enantiomers produced by this process are separated by fractional crystallization of their mandelic acid salts. The enantiomerically pure R-diol then is converted into the corresponding 5-(R)-hydroxymethyl-oxazolidinone by condensation with diethylcarbonate in the presence of sodium methoxide. The 5-(R)-hydroxymethyl-oxazolidinone then is aminated, and the resulting amine acylated in subsequent steps.
Likewise, U.S. Pat. No. 4,948,801, J. Med. Chem., 32, 1673 (1989), and Tetrahedron, 45, 1323 (1989) disclose a method of producing oxazolidinones which comprises reacting an isocyanate (R—N═C═O) with (R)-glycidyl butyrate in the presence of a catalytic amount of a lithium bromide-tributylphosphine oxide complex at 135–145° C. to produce the corresponding 5-(R)-butyryloxymethyl-oxazolidinone. The butyrate ester then is hydrolyzed in a subsequent step to provide the corresponding 5-(R)-hydroxymethyl-oxazolidinone. The 5-(R)-hydroxymethyl-oxazolidinone then is aminated in a subsequent step.
Similarly, the following references disclose variations of the reaction of a carbamate with glycidyl butyrate: Abstracts of Papers, 206th National Meeting of the American Chemical Society, Chicago, Ill., August, 1993; American Chemical Society: Washington, D.C., 1993; ORGN 089; J. Med. Chem., 39, 673 (1996); J. Med. Chem., 39, 680 (1996); International Publications WO93/09103, WO93/23384, WO95/07271, WO96/13502, and WO96/15130; Abstracts of papers, 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, Calif., September, 1995; American Society for Microbiology: Washington, D.C., 1995, Abstract No. F208; Abstracts of Papers, 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, Calif., September, 1995; American Society for Microbiology: Washington, D.C., 1995, Abstract No. F207; Abstracts of Papers, 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, Calif., September, 1995; American Society for Microbiology: Washington, D.C., 1995, Abstract No. F206; Abstracts of Papers, 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, Calif., September, 1995; and American Society for Microbiology: Washington, D.C., 1995, Abstract No. F227. The disclosed reactions use either n-butyllithium, lithium diisopropylamide, or lithium hexamethyldisilazide as the base to generate the nucleophilic anion or the carbamate over a temperature range of −78° C. to −40° C., followed by addition of the glycidyl butyrate at −78° C., and warming to 20–25° C. to produce the 5-(R)-hydroxymethyl-oxazolidinones wherein the ester is cleaved during the reaction.
As stated previously, the 5-(R)-hydroxymethyl-oxazolidinones then are aminated and acylated in subsequent steps. For example, International Publication WO95/07271 discloses the ammonolysis of 5-(R)-methylsulfonyloxymethyl-oxazolidinones. Likewise, U.S. Pat. No. 4,476,136 discloses a method of transforming 5-hydroxymethyl-oxazolidinones to the corresponding 5-(S)-aminomethyl-oxazolidinones (X) by treatment with methanesulfonyl chloride, followed by potassium phthalimide, then followed by hydrazine. J. Med. Chem., 32, 1673 (1989) and Tetrahedron, 45, 1323 (1989) disclose a method of transforming 5-hydroxymethyl-oxazolidinones into the corresponding 5-(S)-acetamidomethyl-oxazolidinones by treating with methanesulfonyl chloride or tosyl chloride, followed by the stepwise addition of sodium azide, trimethylphosphite, or platinum dioxide/hydrogen, and acetic anhydride- or acetyl chloride to give the desired 5-(S)-acetamidomethyl-oxazolidinone. Likewise, U.S. provisional application Ser. No. 60/015,499 discloses a method of preparing 5-(S)-hydroxymethyl-oxazolidinone intermediates, as well as a process to convert these intermediates into 5-aminomethyl-oxazolidinone intermediates which can be acylated to produce pharmacologically active 5-(S)-acetamidomethyl-oxazolidinones. U.S. Pat. No. 3,654,298 discloses the synthesis of 5-alkoxymethyl-3-aryl-oxazolidinones by sodium ethoxide induced cyclization of chlorocarbamates.
The second method (Scheme B) involves condensation of an aromatic carbamate (a) or isocyanate (b) with a protected nitrogen (NP)-containing three-carbon reagent to provide an oxazolidinone having the desired amine functionality at the 5-position (e). For example, J. Med. Chem., 33, 2569 (1990) discloses the condensation of an isocyanate (b) with racemic glycidyl azide (c, NP=N3) to provide a racemic 5-azidomethyl-oxazolidinone (e). Two subsequent steps are required to convert the racemic azidomethyl-oxazolidinone into a racemic 5-acetamidomethyl-oxazolidinone (e, NP=NHAc), which has antibiotic activity.
International Publication WO99/24393 discloses the reaction of a benzylcarbamoyl amine with three carbon reagents containing amines (NP=NH2), acetamides (NP=NHAc), benzalimines (NP=N=C—Ph), or phthalimides. Likewise, Tetrahedron Letters, 37, 7937–40 (1996) discloses a synthesis of acetamidomethyl-oxazolidinones involving the process of condensing a carbamate with 1.1 equivalents of n-butyl lithium (tetrahydrofuran (THF), −78° C.), followed by 2 equivalents of S-glycidylacetamide (a, NP=—NHAc), to give the corresponding 5-(S)-acetamidomethyl-oxazolidinone (e). The S-glycidylacetamide can be made by the procedure disclosed in Jacobsen et. al., Tet. Lett. 37, 7937 (1996).
The S-enantiomer of epoxide (c) (Scheme B, NP=NHCO2t-Bu) is well known in the literature, and has been used to prepare oxazolidinones as disclosed in International Publications WO 99/40094 and WO 99/3764, and German Patent application DE 19802239 A1, although by different routes than that shown in Scheme B. The (S)-epoxide (c) has been prepared by a hydrolytic kinetic resolution of the racemic epoxide as disclosed in WO 00/09463, and from R-glycidol as disclosed in WO 93/01174 and J. Med. Chem., 37, 3707 (1994). However, the (S)-epoxide has not been prepared in crystalline form.
The prior art is silent with respect to the use of carbamates (a) or isocyanates (b) in condensations with tert-butylcarbamoyl-, (BOC), or other carbamoyl-protected nitrogen-containing three-carbon reagents (c,d, NP=NCOOR″) to directly form oxazolidinones (e). The present invention involves condensation of a carbamate with a carbamoyl-protected derivative of glycidylamine or 3-amino-1-halo-2-propanol. The use of the carbamoyl protecting group, and specifically a tert-butylcarbamoyl (BOC) protecting group, results in a more facile reaction, with a greater yield, compared to the prior art. For example, the analogous acetamide reaction (Scheme B, NP=NHAc) typically requires the use of two equivalents of this reagent for the condensation to occur. In contrast, only 1.3 equivalents of the tert-butylcarbamoyl reagent (Scheme B, NP=NHBOC) is required to obtain comparable yields. The success of such a carbamate condensation is both surprising and unexpected because of the apparent steric hindrance of the tert-butylcarbamoyl group.
The present invention also is directed to the conversion of an isocyanate into the (S)-enantiomer of a 5-substituted-oxazolidinone in a single step. The (S)-enantiomers of 5-substituted-oxazolidinones have greater antibiotic activity than the racemates. U.S. Pat. No. 5,332,754 discloses that racemic 5-acetamidomethyl-oxazolidinones can be synthesized in one step by condensation of a carbamate with racemic glycidyl acetamide in the presence of a base, such as an amine, alkali metal hydroxide, an alkali metal alkoxide, and the like, and that it is preferred to carry out the reaction at an elevated temperature, preferably at a temperature between 90° C. and 110° C. The patent provides no yields or description of this process in the examples, and evidence indicates that, under these conditions, rearrangement to an undesired side product occurs. Indeed, the examples do not disclose a one-step process, but disclose multi-step routes that are known to those skilled in the art, including mesylation of a 5-hydroxymethyl-oxazolidinone followed by azide displacement, hydrogenation, and acetylation of the amine.
The present method differs in that a) the reaction is between a protected carbamate (I) and an (S)-glydidyl alkylcarbamate (II), an (S)-chlorohydrin alkylcarbamate (IV), or an (S)-chloroacetate alkylcarbamate (V) (Scheme B, NP=NHalkyl); b) the reaction is between an isocyanate (VI) and an (S)-glydidyl alkylcarbamate (II), an (S)-chlorohydrin alkylcarbamate (IV), or an (S)-chloroacetate alkylcarbamate (V) (Scheme B, NP=NHalkyl), and c) the reaction is performed under conditions such that competing rearrangement to the undesired side products is largely suppressed.